Gestational and Lactational Exposure to Perfluorohexanoic Acid Affects Behavior in Adult Male Mice: A Preliminary Study

Legacy per- and polyfluoroalkyl substances (PFAS) have been associated with increased risk for male-biased neurobehavioral disorders. Industries have effectively replaced them with next-generation PFAS, including perfluorohexanoic acid (PFHxA). Zebrafish studies indicate developmental effects of PFHxA exposure on activity levels; however, the developmental neurotoxicology (DNT) of PFHxA has not been characterized in mammals. Human data reflect the need for mammalian DNT evaluations because PFHxA is found in the serum of pregnant women and in breast milk. Furthermore, postmortem studies show that PFHxA enters the brain, with the cerebellum having particularly elevated concentrations. Given this targeted brain region, we predicted that behavioral effects of PFHxA may target motor domains. To evaluate the effects of developmental PFHxA exposure, we exposed pregnant C57BL/6J mice daily from gestational day 0 through postnatal day (P)21 to vehicle (ddH2O), a lower (0.32 mg/kg of body weight [bw]) or a higher (50 mg/kg of bw) dose of PFHxA. Although this resulted in increases in the brain at P1 in the higher exposure group and in P21 in both exposure groups, by P90, PFHxA levels returned to those in control mice. We observed male-specific effects in the open-field test, the elevated plus maze, and the novel object recognition test in adulthood, with no overt effects in the hang test, inverted screen test, and gait scan. These preliminary findings indicate that PFHxA exposure may cause long-lasting changes in many behavioral domains in a mammalian model, and more research is needed to expand these evaluations to other cognitive domains.